APPLICANT'S ABSTRACT: Fetal alcohol syndrome is a constellation of birth defects caused by maternal alcohol use during pregnancy, and is characterized by intrauterine and postnatal growth deficits, and CNS dysfunctions in the offspring. Tobacco use during pregnancy is also an established cause of fetal growth deficiency, although the toxicological effects of prenatal nicotine exposure on the CNS are not clear. Since tobacco use is highly correlated in women that abuse alcohol during pregnancy, exposure to the combination of these substances may exacerbate the deficiencies associated with alcohol or tobacco use alone. While intrauterine and postnatal growth deficiencies are the most common symptoms of fetal alcohol or tobacco exposure, the cause of these deficiencies unknown. Studies have shown a consistent long-term reduction of insulin-like growth factor-1 (IGF-1), a major mediator of developmental growth, in prenatally ethanol-exposed offspring. The goal of this application is to investigate the actions of in utero ethanol, nicotine, and ethanol/nicotine co-exposure, on the regulation of the IGF and somatotropin gene families, and assess the relationship of changes in tissue and brain IGF and GH regulation, to that of the growth and CNS deficits observed in these offspring. The hypothesis is that fetal exposure to ethanol and nicotine inhibits fetal and neonatal IGF-1 gene expression, thereby reducing tissue availability to IGF-1, and causing or exacerbating the observed growth deficits observed in these offspring. The proposed studies to test this hypothesis include: 1) Examining the effect of fetal ethanol, nicotine and alcohol/nicotine co-exposure, on plasma and somatic tissue specific IGF and GH peptide and gene regulation; 2) Assessing the effect of fetal ethanol and nicotine exposure and co-exposure on changes on CNS neurotrophic expression, with particular emphasis on the IGF and neurotrophic gene families; 3) Examining the specific actions of ethanol and nicotine exposure on growth factor induced cellular function and second messenger systems, in organ culture systems of affected tissues; and 4) Assessing changes in gene expression by differential display PCR, to identify additional candidate genes in these disorders. These studies will provide valuable data which correlate with the endocrine and neuropathological changes seen in fetal alcohol syndrome and smoking in human populations.